Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU4J3ZI)

• DOT Name: Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2)
• Synonyms: Cardiovascular helix-loop-helix factor 1; hCHF1; Class B basic helix-loop-helix protein 32; bHLHb32; HES-related repressor protein 2; Hairy and enhancer of split-related protein 2; HESR-2; Hairy-related transcription factor 2; HRT-2; hHRT2; Protein gridlock homolog
• Gene Name: HEY2
• Related Disease:
  Ependymoma
  Abdominal aortic aneurysm
  Adenocarcinoma
  Adenoma
  Alzheimer disease
  Anaplastic astrocytoma
  Astrocytoma
  Atrial fibrillation
  Atrial septal defect
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Familial adenomatous polyposis
  Hypertrophic cardiomyopathy
  Medulloblastoma
  Neoplasm
  Non-small-cell lung cancer
  Oligoastrocytoma
  Tetralogy of fallot
  Varicose veins
  Ventricular septal defect
  Alcohol dependence
  Benign prostatic hyperplasia
  Brugada syndrome 1
  Hepatocellular carcinoma
  Prostate cancer
  Prostate carcinoma
  Familial thoracic aortic aneurysm and aortic dissection
  Chronic pancreatitis
  T-cell acute lymphoblastic leukaemia
  Ventricular fibrillation
• UniProt ID: HEY2_HUMAN
• Pfam ID: PF07527 ; PF00010
• Sequence:
  MKRPCEETTSESDMDETIDVGSENNYSGQSTSSVIRLNSPTTTSQIMARKKRRGIIEKRR
  RDRINNSLSELRRLVPTAFEKQGSAKLEKAEILQMTVDHLKMLQATGGKGYFDAHALAMD
  FMSIGFRECLTEVARYLSSVEGLDSSDPLRVRLVSHLSTCATQREAAAMTSSMAHHHHPL
  HPHHWAAAFHHLPAALLQPNGLHASESTPCRLSTTSEVPPAHGSALLTATFAHADSALRM
  PSTGSVAPCVPPLSTSLLSLSATVHAAAAAATAAAHSFPLSFAGAFPMLPPNAAAAVAAA
  TAISPPLSVSATSSPQQTSSGTNNKPYRPWGTEVGAF
• Function: Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Cardiogenesis (R-HSA-9733709)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Altered Expression	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[6]
Astrocytoma	DISL3V18	Strong	Biomarker	[6]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[7]
Atrial septal defect	DISJT76B	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Genetic Variation	[10]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[10]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Therapeutic	[12]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Oligoastrocytoma	DISQGE8F	Strong	Biomarker	[6]
Tetralogy of fallot	DISMHFNW	Strong	Altered Expression	[16]
Varicose veins	DISIMBN2	Strong	Altered Expression	[17]
Ventricular septal defect	DISICO41	Strong	Biomarker	[18]
Alcohol dependence	DIS4ZSCO	moderate	Posttranslational Modification	[19]
Benign prostatic hyperplasia	DISI3CW2	moderate	Biomarker	[20]
Brugada syndrome 1	DISKBA7V	moderate	Biomarker	[21]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[14]
Prostate cancer	DISF190Y	moderate	Biomarker	[20]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[20]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Supportive	Autosomal dominant	[22]
Chronic pancreatitis	DISBUOMJ	Limited	Altered Expression	[23]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Biomarker	[24]
Ventricular fibrillation	DIS7IN76	Limited	Genetic Variation	[25]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[32]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[33]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[30]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[34]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[35]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[34]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[34]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[35]
Baicalin	DMY1TLZ	Terminated	Baicalin increases the expression of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[35]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2).	[37]

References

• [1] Study of chromosome 9q gain, Notch pathway regulators and Tenascin-C in ependymomas.J Neurooncol. 2014 Jan;116(2):267-74. doi: 10.1007/s11060-013-1287-z. Epub 2013 Nov 1.
• [2] Downregulation of transforming growth factor, beta receptor 2 and Notch signaling pathway in human abdominal aortic aneurysm.Atherosclerosis. 2012 Apr;221(2):383-6. doi: 10.1016/j.atherosclerosis.2012.01.004. Epub 2012 Jan 9.
• [3] Leptin enhances N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced tumour growth in gastric mucosa of male Sprague-Dawley rats.Mol Biol Rep. 2019 Dec;46(6):5967-5975. doi: 10.1007/s11033-019-05030-z. Epub 2019 Aug 23.
• [4] Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome.Endocr Relat Cancer. 2015 Aug;22(4):531-43. doi: 10.1530/ERC-15-0163. Epub 2015 May 15.
• [5] MicroRNA-98 reduces amyloid -protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice.Int J Mol Med. 2019 Jan;43(1):91-102. doi: 10.3892/ijmm.2018.3957. Epub 2018 Oct 24.
• [6] Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres.Genes Cancer. 2010 Aug;1(8):822-35. doi: 10.1177/1947601910383564.
• [7] Brugada syndrome risk loci seem protective against atrial fibrillation.Eur J Hum Genet. 2014 Dec;22(12):1357-61. doi: 10.1038/ejhg.2014.46. Epub 2014 Mar 26.
• [8] Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome.Mamm Genome. 2004 Sep;15(9):711-6. doi: 10.1007/s00335-004-2389-x.
• [9] Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation.Anticancer Res. 2010 Oct;30(10):3853-67.
• [10] Chromosome 5 allele loss at the glucocorticoid receptor locus in human colorectal carcinomas.Biochem Biophys Res Commun. 1988 Jan 29;150(2):591-8. doi: 10.1016/0006-291x(88)90434-2.
• [11] Notch Signaling Target Genes are Directly Correlated to Esophageal Squamous Cell Carcinoma Tumorigenesis.Pathol Oncol Res. 2015 Apr;21(2):463-7. doi: 10.1007/s12253-014-9849-8. Epub 2014 Nov 1.
• [12] CHF1/Hey2 promotes physiological hypertrophy in response to pressure overload through selective repression and activation of specific transcriptional pathways.OMICS. 2009 Dec;13(6):501-11. doi: 10.1089/omi.2009.0086.
• [13] Endothelial Cells Promote Formation of Medulloblastoma Stem-Like Cells via Notch Pathway Activation.J Mol Neurosci. 2017 Oct;63(2):152-158. doi: 10.1007/s12031-017-0965-2. Epub 2017 Aug 30.
• [14] HEY2 acting as a co-repressor with smad3 and smad4 interferes with the response of TGF-beta in hepatocellular carcinoma.Am J Transl Res. 2019 Jul 15;11(7):4367-4381. eCollection 2019.
• [15] LncRNA PRNCR1 interacts with HEY2 to abolish miR-448-mediated growth inhibition in non-small cell lung cancer.Biomed Pharmacother. 2018 Nov;107:1540-1547. doi: 10.1016/j.biopha.2018.08.105. Epub 2018 Sep 5.
• [16] Duplication of HEY2 in cardiac and neurologic development.Am J Med Genet A. 2015 Sep;167A(9):2145-9. doi: 10.1002/ajmg.a.37086. Epub 2015 Apr 1.
• [17] Forkhead box C2 promoter variant c.-512C>T is associated with increased susceptibility to chronic venous diseases.PLoS One. 2014 Mar 7;9(3):e90682. doi: 10.1371/journal.pone.0090682. eCollection 2014.
• [18] A Novel Somatic Variant in HEY2 Unveils an Alternative Splicing Isoform Linked to Ventricular Septal Defect.Pediatr Cardiol. 2019 Jun;40(5):1084-1091. doi: 10.1007/s00246-019-02099-y. Epub 2019 Apr 6.
• [19] Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence.Alcohol Clin Exp Res. 2006 Apr;30(4):587-91. doi: 10.1111/j.1530-0277.2006.00068.x.
• [20] Repression of androgen receptor activity by HEYL, a third member of the Hairy/Enhancer-of-split-related family of Notch effectors.J Biol Chem. 2011 May 20;286(20):17796-808. doi: 10.1074/jbc.M110.198655. Epub 2011 Mar 17.
• [21] Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death.Nat Genet. 2013 Sep;45(9):1044-9. doi: 10.1038/ng.2712. Epub 2013 Jul 21.
• [22] Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms. Genet Med. 2021 Jan;23(1):103-110. doi: 10.1038/s41436-020-00939-4. Epub 2020 Aug 21.
• [23] Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis.J Pathol. 2008 Feb;214(3):312-9. doi: 10.1002/path.2293.
• [24] Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines.Exp Cell Res. 2007 Aug 15;313(14):3141-52. doi: 10.1016/j.yexcr.2007.04.027. Epub 2007 May 5.
• [25] A Common Variant in SCN5A and the Risk of Ventricular Fibrillation Caused by First ST-Segment Elevation Myocardial Infarction.PLoS One. 2017 Jan 13;12(1):e0170193. doi: 10.1371/journal.pone.0170193. eCollection 2017.
• [26] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [27] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [28] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [29] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [30] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [31] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [32] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [33] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [34] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [35] The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. J Cell Biochem. 2009 Mar 1;106(4):682-92. doi: 10.1002/jcb.22065.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.